The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab 280: E827-E847, 2001.-The ability to ensure continous availability of energy despite highly variable supplies in the environment is a major determinant of the survival of all species. In higher organisms, including mammals, the capacity to efficiently store excess energy as triglycerides in adipocytes, from which stored energy could be rapidly released for use at other sites, was developed. To orchestrate the processes of energy storage and release, highly integrated systems operating on several physiological levels have evolved. The adipocyte is no longer considered a passive bystander, because fat cells actively secrete many members of the cytokine family, such as leptin, tumor necrosis factor-␣, and interleukin-6, among other cytokine signals, which influence peripheral fuel storage, mobilization, and combustion, as well as energy homeostasis. The existence of a network of adipose tissue signaling pathways, arranged in a hierarchical fashion, constitutes a metabolic repertoire that enables the organism to adapt to a wide range of different metabolic challenges, such as starvation, stress, infection, and short periods of gross energy excess. leptin; tumor necrosis factor-␣; interleukins; obesity; insulin resistance OVERVIEW Unraveling the diverse hormonal and neuroendocrine systems that regulate energy balance and body fat has been a long-standing challenge in biology, with obesity as an increasingly important public health focus (12). Adipose tissue is the body's largest energy reservoir. For example, an adult with 15 kg of body fat has Ͼ460 MJ (110,000 kcal) of lipid fuel stores, which could provide 8.37 MJ (2,000 kcal) daily for ϳ2 mo (75, 129). The primary role of adipocytes is to store triacylglycerol during periods of caloric excess and to mobilize this reserve when expenditure exceeds intake. Mature adipocytes are uniquely equipped to perform these functions. They possess the full complement of enzymes and regulatory proteins needed to carry out both lipolysis and de novo lipogenesis. In fat cells, the regulation of these processes is exquisitely responsive to hormones, cytokines, and other factors that are involved in energy metabolism (87). The ability to carry out these functions is acquired during embryonic development in preparation for the postnatal period, when an adipose energy reserve becomes necessary. Major expansion of the white adipocyte population is delayed until shortly after birth, although preadipocytes first appear late in embryonic life (22).The present review will focus on the evidence for the synthesis and secretion by white adipocytes of endocrine, paracrine, and autocrine signals implicated in energy balance regulation, with special reference to cytokines. The interactions between these adipose tissue-derived mediators and other neuroendocrine pathways will be examined. Furthermore, the metabolic alterations in adipose tissue signaling leading...

BACKGROUND Genomic studies have yielded important insights into the pathogenesis of obesity. Circulating microRNAs (miRNAs) are valuable biomarkers of systemic diseases and potential therapeutic targets. We sought to define the circulating pattern of miRNAs in obesity and examine changes after weight loss. METHODS We assessed the genomewide circulating miRNA profile cross-sectionally in 32 men and after surgery-induced weight loss in 6 morbidly obese patients. The most relevant miRNAs were cross-sectionally validated in 80 men and longitudinally in 22 patients (after surgery-induced weight loss). We evaluated the effects of diet-induced weight loss in 9 obese patients. Thirty-six circulating miRNAs were associated with anthropometric variables in the initial sample. RESULTS In the validation study, morbidly obese patients showed a marked increase of miR-140-5p, miR-142-3p (both P < 0.0001), and miR-222 (P = 0.0002) and decreased levels of miR-532–5p, miR-125b, miR-130b, miR-221, miR-15a, miR-423-5p, and miR-520c-3p (P < 0.0001 for all). Interestingly, in silico targets leukemia inhibitory factor receptor (LIFR) and transforming growth factor receptor (TGFR) of miR-140-5p, miR-142-3p, miR-15a, and miR-520c-3p circulated in association with their corresponding miRNAs. Moreover, a discriminant function of 3 miRNAs (miR-15a, miR-520c-3p, and miR-423-5p) was specific for morbid obesity, with an accuracy of 93.5%. Surgery-induced (but not diet-induced) weight loss led to a marked decrease of miR-140-5p, miR-122, miR-193a-5p, and miR-16-1 and upregulation of miR-221 and miR-199a-3p (P < 0.0001 for all). CONCLUSIONS Circulating miRNAs are deregulated in severe obesity. Weight loss–induced changes in this profile and the study of in silico targets support this observation and suggest a potential mechanistic relevance.

Context: Body mass index (BMI) is widely used as a measure of overweight and obesity, but underestimates the prevalence of both conditions, defined as an excess of body fat. Objective: We assessed the degree of misclassification on the diagnosis of obesity using BMI as compared with direct body fat percentage (BF%) determination and compared the cardiovascular and metabolic risk of non-obese and obese BMI-classified subjects with similar BF%. Design: We performed a cross-sectional study. Subjects: A total of 6123 (924 lean, 1637 overweight and 3562 obese classified according to BMI) Caucasian subjects (69% females), aged 18-80 years. Methods: BMI, BF% determined by air displacement plethysmography and well-established blood markers of insulin sensitivity, lipid profile and cardiovascular risk were measured. Results: We found that 29% of subjects classified as lean and 80% of individuals classified as overweight according to BMI had a BF% within the obesity range. Importantly, the levels of cardiometabolic risk factors, such as C-reactive protein, were higher in lean and overweight BMI-classified subjects with BF% within the obesity range (men 4.3 ± 9.2, women 4.9 ± 19.5 mg l À1 ) as well as in obese BMI-classified individuals (men 4.2 ± 5.5, women 5.1 ± 13.2 mg l À1 ) compared with lean volunteers with normal body fat amounts (men 0.9 ± 0.5, women 2.1 ± 2.6 mg l À1 ; Po0.001 for both genders). Conclusion: Given the elevated concentrations of cardiometabolic risk factors reported herein in non-obese individuals according to BMI but obese based on body fat, the inclusion of body composition measurements together with morbidity evaluation in the routine medical practice both for the diagnosis and the decision-making for instauration of the most appropriate treatment of obesity is desirable.